This proposal will use the interferon-? binding protein from ectromelia virus (IFN-?BPECTV) to design new cytokine antagonists and improved research reagents with broad applications to many disciplines. Preliminary structural studies on IFN-?BPECTV have revealed a novel tetrameric structure. The structure will be used to engineer IFN-?BPECTV-based reagents that block signaling by the immunosuppressive cytokine, IL-10. These poxvirus-based IL-10 blocking proteins will be tested for their ability to resolve chronic LCMV infections in mice. Using computational and library screening methodology, hetero-tetrameric D3 assembly reagents will also be developed and tested in the LCMV infection model. These studies will validate the importance of D3-based reagents and provide new insights into LCMV induced T-cell exhaustion. This is important as T-cell exhaustion also occurs during hepatitis C and HIV infections in humans. PUBLIC HEALTH RELEVANCE: This proposal will design and test cytokine blocking reagents that are based on proteins in poxviruses that efficiently antagonize cytokines. This work will provide new research reagents to better study T-cell exhaustion and a broad number of other problems in human health. In particular, these studies could help us understand how to harness the immune system to eliminate hepatitis C and/or HIV infections.